Polypetides that include conformation-constraining groups which flank a protein-protein interaction site

ABSTRACT

Homologs and analogs of naturally-occurring stem cell factor polypeptides contain one or more interaction sites of the natural counterpart. The interaction sites are flanked by conformation-constraining moieties, such as proline or cysteine.

This application is a continuation of U.S. Ser. No. 08/532,818, filedMay 3, 1996, which is a 371 of PCT/US94/04294, filed Apr. 21, 1994,which is a continuation-in-part of U.S. Ser. No. 08/143,364, filed Oct.29, 1993 (now abandoned). Applicants claim priority to theabove-identified applications.

BACKGROUND OF THE INVENTION

The present invention relates to improving the bioactivity of a diverserange of peptides and proteins in their various forms (collectively"polypeptides") by employing conformation-constraining residues to flanksites of the polypeptide that are involved in protein-proteininteractions.

Protein-protein interactions are crucial to almost every physiologicaland pharmacological process. These interactions often are characterizedby very high affinity, with dissociation constants in the low nanomolarto subpicomolar range. Such strong affinity between proteins is possiblewhen a high level of specificity allows subtle discrimination amongclosely related structures. The interaction sites of several proteinpairs have been identified by strategies such as chemical modificationof specific amino acid residues, site-directed mutagenesis, peptidesynthesis, X-ray diffraction studies and theoretical approaches.

Certain general structural features have emerged from these studies. Forexample, some interactions involve more than one interaction site. Thephrase "interaction site" is used in this description to denote a sitecomprised of amino acid residues which is involved in the interactionbetween two proteins. The high affinities at these interaction sites areattributed to several factors, including shape complementarity,electrostatic and hydrogen bond links, and burial of hydrophobic groups.A protein-protein interaction may involve one or more of these factorsat each interaction site.

The amino acids of an interaction site usually constitute a smallproportion of the total amino acids present in the polypeptide.Typically, the number of amino acid residues in a single interactionsite ranges from three to six. These residues often are connected by thepeptide bonds of adjacent residues in a continuous interaction site.Alternatively, the amino acid residues involved in the interaction arenot linked directly by peptide bonds, but rather are brought together bythe three-dimensional folding of the protein and are known as"discontinuous" sites. Due to this extensive variability, it has beendifficult to identify the amino acids of interaction sites.

The chemical nature of the side chains of the amino acid residuescontributes significantly to the interaction, although main chain atomsalso can be involved. Positively charged residues (such as lysine,arginine and histidine) can associate through salt bridge links withnegatively charged residues (such as aspartic acid and glutamic acid).Additionally, the side chains of leucine, isoleucine, methionine,valine, phenylalanine, tyrosine, tryptophan and proline are ofteninvolved in hydrophobic interactions. Precise alignment of atoms betweenthe interaction sites of one protein and its partner also allow multipleVan der Waals interactions and thus increase the likelihood of strongbinding between the two interaction partners.

Bernstein et al., Nature 340: 482 (1989), proposed a role for methioninein protein-protein interactions, whereby clusters of methionine residuesin the 54,000 MW signal recognition particle play a key role in therecognition of signal peptides. Because of the unique flexibility oftheir side chains, methionine residues located on one face of thesurface of the amphiphilic helix provide a malleable, nonpolar surface.It was postulated that in the binding process, this surface can adaptitself to peptide partners of various dimensions and thus conform to thestructure of the signal peptide. A similar mechanism was suggested forthe ability of calmodulin to interact with various protein partners. Thebinding site of calmodulin contains eight exposed methionine residues.Such flexibility of the side chain of methionine might be attributableto the presence of the sulfur atom.

A large number of proteins are synthesized as inactive precursors andactivated in vivo only where and when they are needed. Accordingly,their activity is strictly regulated so as to contribute to the overallcontrol of physiological processes. Some of these proteins are activatedby the action of specific proteinases, and the interaction between thecleavage site and the proteinases should be deemed highly specific.Therefore, the regions around these activation sites form another groupof protein-protein interaction sites.

As described above, the diverse properties of the various amino acidsaffect the characteristics of the interaction site, as well as thepolypeptide as a whole. One amino acid residue that has wholly uniquestructural characteristics is proline.

Proline is the only common imino acid found in proteins. The side chainof proline is bonded to the tertiary nitrogen in a cyclic pyrrolidinering. This ring inhibits free rotation about the C.sub.α --N bond andthus restricts the range of allowable conformations of the polypeptidebackbone. The pyrrolidine ring also constrains the conformation of theadjacent residues. The imino nitrogen of the proline residue lacks aproton that is required for hydrogen bond formation in both theα-helical and β-pleated sheet conformations. Accordingly, proline isoften called a "helix breaker." Additionally, the carbonyl oxygen atomof the amino acid residue immediately preceding proline in thepolypeptide is more electronegative than carbonyl oxygen atoms precedingother amino acid residues. As a result, this carbonyl group has anenhanced tendency to accept and form strong hydrogen bonds.

Proline also differs from other amino acid residues in terms ofpermissible bond configuration. The partial double bond character ofpeptide bonds prevents free rotation and can result in either cis ortrans configurations around the peptide bond. In the cis configuration,the C.sub.α atoms of adjacent amino acid residues are closer than in thetrans configuration. This "closeness" often causes steric hindrancebetween the side chains on the two C.sub.α atoms. Accordingly, almostall peptide bonds are in the trans configuration, so that the C.sub.αatoms of adjacent amino acid residues are separated by the greatestdistance possible. In contrast to most amino acids, proline residues canmore readily assume cis configurations because the amide nitrogen ispart of a ring. Of course, the ring still imposes conformationalconstraints by inhibiting free rotation around the α carbons ofadjoining residues.

Previous studies have implicated praline residues at some interactionsites of certain classes of molecules. Praline has been thought to berequired in the interaction site geometry of a class of proteins knownas the serine proteinase inhibitors. This proposal was later retractedbecause praline was not universally present near interaction sites. SeeLaskowski and Kato, Ann. Rev. Biochem. 49: 593-626 (1980). Aproline-directed arginyl cleavage at monobasic processing sites has alsobeen proposed. See Schwartz, FEBS Letts. 200: 1-10 (1986). About a thirdof the monobasic processing sites contain a praline residue either justbefore or just after the basic residue. A praline residue was also foundto be important in the processing of the signal peptide of humanlysozyme. Several proline-directed kinases which phosphorylate theirsubstrates at the residues that are immediately followed by prolineresidues have been purified from various sources. In some cases, aproline residue two or three residues before the phosphorylation sitealso appears to have importance. But these phosphorylation sites includeonly a few examples. Hence, it was assumed heretofore that proline wasinvolved in only a small number of specific cases.

Proline is known to be a helix breaker because it has a secondary aminegroup, which cannot form hydrogen bonds with neighboring CO groups asother amino acids do. Still, proline is found in some of the surfacehelices of soluble proteins. The "kink" induced by the proline may helpin helical packing by wrapping the helix around a protein core.Recently, the importance of proline residues in transmembrane heliceshas been noted. Interestingly, the putative transmembrane helices of ionchannel peptides have a proline residue within their sequence. Theseproline residues tend to be conserved among homologous proteins, whilesimilar transmembrane helices of non-transport proteins seem to bedevoid of proline residues. The convex side of a proline-containinghelix is packed against neighboring transmembrane helices. The uniquegeometry of the proline frees a non-hydrogen bonded carbonyl oxygen inthe helix backbone for binding to a cation.

Because an interaction site of a polypeptide is so difficult toidentify, the interaction sites of most proteins have remained unknown.In one of its aspects, the present invention takes advantage of prolinepositioning to identify interaction sites of proteins. The uniqueproperties of proline have a stabilizing function which, according toanother aspect of the present invention, can be used to engineer novelpolypeptides based on biologically-active polypeptides. Thesebiologically-active polypeptides possess a functional activity andinclude naturally-occurring polypeptides or polypeptides derivedtherefrom. These novel polypeptides can have improved activities,stabilities or other properties of interest.

SUMMARY OF THE INVENTION

It thus is an object of the present invention to provide polypeptideswhich can mimic or antagonize an activity of biologically-activepolypeptide, such as a naturally-occurring polypeptide or a polypeptidederived therefrom.

It is another object to provide polypeptides havingconformation-constraining residues which flank one or more interactionsites of the polypeptide.

It is still another object of the present invention to providepolypeptide regions that act as protein-protein interaction sites.

It is also an object of the invention to provide an approach foridentifying and synthesizing peptides containing interaction sites.

It is yet another object of the present invention to provide a methodfor synthesizing polypeptides that are flanked byconformation-constraining moieties.

In accomplishing these and other objects, there have been provided, inaccordance with one aspect of the present invention, analogs ofbiologically-active polypeptides, such as naturally-occurringpolypeptides or polypeptides derived therefrom, comprising aninteraction site and conformation-constraining moieties flanking theinteraction site. The analog typically is shorter than thebiologically-active polypeptide, but this need not always be the case.Preferably, the analogs are no more than 30 amino acid residues long,and the conformation-constraining moieties are within 7 amino acidresidues of the interaction site. It is also preferred that theconformation-constraining moieties are proline residues.

The analogs can mimic or antagonize an activity of a biologically-activepolypeptide. Analogs are provided for that mimic the activity ofhypotensive peptides, fibrinolytic peptides, chemotactic peptides,growth promoter peptides, lymphocyte mitogens, immunomodulator peptides,clot-inducing peptides, cardiac stimulant peptides, sweet peptides,taste-modifier peptides, macrophage activating peptides, anti-tumorpeptides, Relaxin, platelet aggregation inhibitors, Leech AntiplateletProtein, Moubatin, and Alzeimer's disease peptides. Analogs are alsoprovided for that antagonize or inhibit the activity of fertilitypeptides, inflammatory peptides, platelet derived growth factor, bloodproteins, and angiotensin II. The inhibited blood proteins includeFactor V, Factor VIIa, Factor VIII, Factor IXa, Factor Xa, fibrinogen,prothrombin, von Willebrand Factor and Platelet Glycoprotein IIb.

Analogs are obtainable, pursuant to the present invention, by the stepsof identifying an interaction site of a biologically-active polypeptide,such as a naturally-occurring polypeptide or polypeptide derivedtherefrom, and obtaining a polypeptide that (i) has a different lengththan the biologically-active polypeptide and (ii) contains theinteraction site of the biologically-active polypeptide flanked byconformation-constraining moieties.

In accordance with another aspect of the present invention, there areprovided homologs of biologically-active polypeptides, such asnaturally-occurring polypeptides or polypeptides derived therefrom,which have at least one interaction site. The homologs comprise most orall of the sequence of the biologically-active polypeptide along withconformation-constraining moieties flanking the interaction site. Theconformation-constraining moieties can be placed in biologically-activepolypeptides that lack such moieties altogether or possess such moietiesin an undesired location or an undesired form. Preferably, theconformation-constraining moieties comprise proline residues. Forexample, proline could be used to replace a cysteine that is involved ina disulfide bound when the interaction site is near the cysteine.

The homologs of the present invention can mimic activities ofbiologically-active polypeptides. In particular, homologs are providedfor that mimic the activity of analgesics, appetite suppressants, B-celldifferentiating peptides, hypocalcemic agents, hypoglycemicpotentiators, hypotensive agents, immune potentiators andsomatostatin-like peptides. Additionally, homologs can antagonize orinhibit activities of biologically-active polypeptides. One such homologis a gastrin-releasing peptide antagonist.

Homologs within the present invention are obtainable by the steps of (i)identifying an interaction site of a biologically-active polypeptide,such as a naturally-occurring polypeptide or polypeptide derivedtherefrom and (ii) flanking the interaction site withconformation-constraining moieties.

DETAILED DESCRIPTION OF PREFERRED EMBODIMENTS

It now has been discovered that the biological activity of polypeptidescan be enhanced several fold by incorporating proline or otherconformation-constraining moieties into regions that flank theinteraction site(s) of a given polypeptide. Such enhancement in activitymakes it possible to design drugs with greater specificity at decreasedcost. Proline residues and other conformation-constraining moietiesrestrict the number of conformations of the polypeptides to increase thelikelihood of the favorable conformation occurring.

The term "polypeptide" is used here to denote allpharmacologically-acceptable forms, such as non-toxic acid or baseaddition salts.

According to the present invention, an "analog" is a polypeptidecontaining an interaction site that was obtained or derived from abiologically-active polypeptide, but differs in length from thebiologically-active polypeptide upon which it is based. An analog thatis shorter than the native polypeptide is referred to as a "truncatedanalog." In accordance with the present invention, the interactionsite(s) of an analog are flanked by conformation-constraining moieties.Typically, these analogs are no more than 30 amino acid residues long,preferably, no longer than 25 amino acid residues and, even morepreferably, are no longer than 15 amino acid residues. Theconformation-constraining moieties should be within 7 amino acidresidues of the interaction site. Preferably, theconformation-constraining moieties are within 4 amino acid residues ofthe interaction site and, even more preferably, within one amino acidresidue of the interaction site. Additionally, the amino acids of theinteraction site can be changed, preferably in accordance with theconservative substitutions disclosed herein.

The present invention also is useful for constructing "homologs" ofbiologically-active polypeptides. A homolog has most or all of thesequence of another, biologically-active polypeptide which contains aninteraction site, but the interaction site of the homolog is flanked byconformation-constraining moieties in a manner distinct from the otherpolypeptide. A homolog thus is a variant formed by placingconformation-constraining moieties adjacent or proximate to theinteraction site of the homolog, according to the present invention.This can be done even with polypeptides wherein interaction sites arenot flanked with such moieties in the native state. Accordingly,conformation-constraining moieties can be employed advantageously withall polypeptides having interaction sites, regardless of whether thepolypeptide is of natural, recombinant or synthetic origin. Theconformation-constraining moieties employed should be sufficientlyadjacent or proximate to the interaction site to permit the moieties toexert influence on the site. Homologs can have lengths that differ fromthat of the native polypeptide. That is, the homolog can be longer orshorter than the native polypeptide. For example, the homolog cancontain amino acids in addition to those present in the nativepolypeptide. Finally, the amino acids of the interaction site can bechanged, preferably in accordance with the conservative substitutionsdisclosed herein.

As is apparent from the above discussion, the concepts implicated by theterms "analog," "truncated analog" and "homolog" are not mutuallyexclusive. For example, a homolog according to the present inventioncould comprise a polypeptide where prolines are inserted in thepolypeptide sequence. As stated above, a polypeptide modified in thisway can also have amino acids removed from the sequence. Thus, a homologcan be shortened so that its length is less than that of the nativepolypeptide. Other modifications will become apparent to the skilledartisan in view of the present specification.

The present invention employs to advantage the unique structures andcharacteristics of proline. In proteins, proline residues often affectthe conformation of protein-protein interaction sites by breaking thecontinuity of the adjacent secondary structures, such as α-helices.Small polypeptides often do not have secondary structures, however.Nevertheless, the presence of proline residues in both large and smallpeptides is useful, pursuant to the present invention, both for locatingthe interaction sites of these polypeptide and for stabilizinginteraction regions.

The present invention thus encompasses a method for altering orstabilizing the reactivity of interaction sites for bioactivity, bysynthesizing a sequence of amino acids where (i) a part of the sequencecomprises an interaction site, (ii) the interaction site is flanked onboth sides by sequences that contain a proline residue or otherconformation-constraining moiety, and (iii) each such moiety is locatedsufficiently near an interaction site to exert influence over the site.In accordance with the present invention, sequences as thus describedcan be placed adjacent or proximate to an interaction site on apolypeptide to alter or stabilize the specific reactivity of the site.Such a site can be referred to as being "flanked" or "bracketed" by theconformation-constraining moiety. In this specification, aconformation-constraining moiety so inserted is often referred to as a"bracket."

The present invention also relates to the identification of interactionsites in polypeptides. The interaction site of a polypeptide can beascertained by searching for flanking proline residues or otherconformation-constraining moieties, such as cysteine. For instance, apeptide region that is flanked by two proline residues, a prolineresidue and a cysteine residue or two cysteine residues is at least aputative interaction site. Typically, the regions that are flanked bythese residues comprise fifteen or fewer amino acids.

Via methodology within the present invention, it is possible to producenovel, multifunctional polypeptides, or polypeptides with new functionalproperties, by inclusion of interaction sites with proline or otherconformation-constraining brackets into the polypeptide. Thepolypeptides of the present invention can be administered in variousnon-toxic forms, such as acid or base addition salts.

The inclusion of proline or other constraining brackets allows theinteraction site to be altered, which permits targeting of thepolypeptide to certain interaction partners found on specific cell ortissue types. Targeting of polypeptide drugs to a specific type of cellor tissue would result in considerable reduction of both the effectivedose and the likelihood of side effects. Polypeptides can be customdesigned, in accordance with the present invention, to flank aninteraction site with brackets to alter or otherwise affect the flankedsite.

It is often desirable to insert alanine residues adjacent to the prolinebrackets. That is, the alanine residues would flank theproline-bracketed interaction sites. The alanine residues serve toprotect the amino- and carboxy-terminal ends of the polypeptide.

Several polypeptides having specific, desired activity have beenidentified. Polypeptides of the structures described here can besynthesized routinely, using solid-phase or solution-phase peptidesynthesis. The final peptide preparation can be purified using variouschromatographic methods including high performance liquid chromatographyand adsorption chromatography. The purity and the quality of thepeptides can be confirmed by amino acid analyses, molecular weightdetermination, sequence determination and mass spectrometry.

The analogs and homologs of the present invention can be combined with avariety of carriers. Pharmaceutically-acceptable carriers includeaqueous solutions, non-toxic excipients, including salts, preservatives,buffers and the like, as described in REMINGTON'S PHARMACEUTICALSCIENCES, 15th Ed. Easton: Mack Publishing Co. pp 1405-1412 and1461-1487 (1975) and THE NATIONAL FORMULARY XIV., 14th Ed. Washington:American Pharmaceutical Association (1975), the contents of which arehereby incorporated by reference. Examples of non-aqueous solvents arepropylene glycol, polyethylene glycol, vegetable oil and injectableorganic esters such as ethyloleate. Aqueous carriers include water,alcoholic/aqueous solutions, saline solutions, parenteral vehicles suchas sodium chloride, Ringer's dextrose, etc. Intravenous vehicles includefluid and nutrient replenishers. Preservatives include antimicrobials,anti-oxidants, chelating agents and inert gases. The pH and exactconcentration of the various components of the binding composition areadjusted according to routine skills in the art. See GOODMAN ANDGILMAN'S THE PHARMACOLOGICAL BASIS FOR THERAPEUTICS (7th ed.).

Structural Modifications

Protein interaction sites in great diversity have been identified viathe present invention and are described in greater detail below. Theseinteraction sites and surrounding sequences can be altered further inview of the substitution considerations described below.

Conservative substitutions--Amino acids having similar properties can beemployed to make conservative substitutions in the sequence of apolypeptide. Such substitutions can help in retaining or, in some cases,enhancing biological properties of the polypeptides. The replacement ofone amino acid residue by another residue of the same group areconsidered conservative substitutions, as set forth below:

group (a)--Lys, Arg, Homoarg and Orn;

group (b)--Leu, Ile, Val, Met and Norleu;

group (c)--Tyr, Phe and Trp;

group (d)--Glu and Asp;

group (e)--Gln and Asn;

group (f)--Ser and Thr; and

group (g)--Ala and Gly.

The abbreviations are as follows: Ala=alanine; Arg=arginine;Asn=asparagine; Asp=aspartic acid; Gln=glutamine; Glu=glutamic acid;Gly=glycine; His=histidine; Homoarg=homoarginine; Ile=isoleucine;Leu=leucine; Lys=lysine; Met=methionine; Norleu=norleucine;Orn=ornithine; Phe=phenylalanine; Pro=proline; Ser=serine;Thr=threonine; Trp=tryptophan; Tyr=tyrosine and Val=valine.

It must be noted, however, that the greater the number of substitutionsmade in the interaction site, the less predictable its activity will be.Generally, it is preferred to make no more than two amino acidsubstitutions in the sequence of a given interaction site. In somebiologically-active polypeptides, both proline residues and disulfidebridges serve to constrain the conformation of interaction sites. Anaturally-occurring interaction site may be bracketed by (1) two prolineresidues, (2) a proline residue and a cysteine residue (in a disulfidelinkage) or (3) two cysteine residues in disulfide linkage, either inlinkage with each other or with other residues in the polypeptide, asappropriate.

In most of the polypeptides structures presented here, the prolineresidues are employed as non-cyclic structural constraints. This meansthat the constraining proline brackets are only bound to other aminoacids by the peptide bond. The present invention also comprehends othernon-cyclic structural constraints, such as L-N-methylated amino acidresidues or spirolactams. These moieties can be introduced into thepeptide backbone. Additionally, side chains can be cyclized to thebackbone so as create a L-γ-lactam moiety on each side of theinteraction site. See, generally, Hruby et al., "Applications ofSynthetic Peptides," in SYNTHETIC PEPTIDES: A USER'S GUIDE 259-345 (W.H. Freeman & Co. 1992). Cyclization also can be achieved, for example,by formation of cystine bridges, coupling of amino and carboxy terminalgroups of respective terminal amino acids, or coupling of the aminogroup of a Lys residue or a related homolog with a carboxy group of Asp,Glu or a related homolog. Coupling of the α-amino group of a polypeptidewith the ε-amino group of a lysine residue, using iodoacetic anhydride,can be also undertaken. See Wood and Wetzel, Int'l J. Peptide ProteinRes. 39: 533-39 (1992).

The conformational restraints imposed by cyclization arise from covalentcross-linking may reduce flexibility too much and even result in strainat the interaction site, which could lead to a loss of function. Prolinebrackets, on the other hand, allow for some flexibility without causingsignificant strain at the interaction site. Accordingly, proline ispreferred for use in the present invention.

A key aspect of the present invention is the recognition that smallerpolypeptides show a considerable amount of flexibility and,consequently, can exist in solution in a very high number of conformers,generated by rotation around all of the N--C.sub.α and C.sub.α --C bondsof the peptide backbone. Pursuant to the present invention, thebracketing of an interaction site by either L- or D-proline imposesconstraints on the polypeptide, thereby reducing the number of possibleconformers and increasing the relative population that has the favored,active conformation. The introduction of proline brackets to alter orstabilize bioactivity at interaction sites can potentiate the specificaction of drugs and other biologically-active agents.

Synthesis of Peptides

Polypeptides within the present invention can be generated directly fromthe native polypeptides by chemical cleavage, by proteolytic enzymedigestion, and by combinations thereof. Additionally, such polypeptidescan be created by synthetic techniques or recombinant techniques whichemploy genomic or cDNA cloning methods.

For example, methods of synthesizing polypeptides directly from aminoacid derivatives are widely known. Such synthesis can be undertaken withautomated peptide synthesizers. Peptides of the structures given belowcan be routinely synthesized using solid phase or solution phase peptidesynthesis.

Site-specific and region-directed mutagenesis techniques also can beemployed. See CURRENT PROTOCOLS IN MOLECULAR BIOLOGY vol. 1, ch. 8(Ausubel et al. eds., J. Wiley & Sons 1989 & Supp. 1990-93); PROTEINENGINEERING (Oxender & Fox eds., A. Liss, Inc. 1987). In addition,linker-scanning and polymerase chain reaction ("PCR") mediatedtechniques can be used for purposes of mutagenesis. See PCR TECHNOLOGY(Erlich ed., Stockton Press 1989); CURRENT PROTOCOLS IN MOLECULARBIOLOGY, vols. 1 & 2, loc. cit.

The final peptide preparation can be purified using variouschromatographic methods including high performance liquid chromatographyand adsorption chromatography. The purity and the quality of thepeptides can be confirmed by amino acid analyses, mass spectrometry,molecular weight determination and sequence determination.

Polypeptides within the present invention can be administered in themanner that natural peptides are administered. The method ofadministration will depend on the site at which the reaction is tooccur, as well as the desired result.

The present invention is further illustrated by the following examples.These examples concern the interaction sites of various types ofproteins, and are provided to give further insights into the invention.These examples do not limit the scope of the invention.

EXAMPLE I Effects of Proline on Cellular Adhesion Proteins

Cellular adhesive interactions are involved in tissue development,hemostasis, tumor cell metastasis, intercellular communication, and hostdefense mechanisms of multicellular organisms. The recognition ofextracellular ligands by cell surface receptors is a common butmandatory step in such interactions.

Most of these interactions are mediated by a family of closely relatedadhesive receptors and have therapeutic implications. For example, thedevelopment of antiplatelet drugs is important in the prevention andtreatment of atherosclerosis, myocardial infarction, stroke and cancer.The polypeptides involved in platelet aggregation and other adhesiveinteractions are structurally and immunologically related, and plateletaggregation, one of the specialized adhesive reactions, is easy tomonitor by conventional techniques.

Several recognition sequences are involved in the adhesive interactions.The Arg-Gly-Asp (RGD) (SEQ ID NO: 1) tripeptide is a common molecularrecognition site implicated in several of these interactions. But thepresence of the RGD sequence alone does not necessarily result in theparticipation of the proteins in adhesive reactions. It appears that thepresence of other amino acid residues around the RGD sequence may beimportant for the presentation of this site. Most adhesive proteinscontain at least one proline residue around the RGD sequence, onenotable exception being fibrinogen.

Other classes of proteins, such as the disintegrins, possess the RGDtripeptide. Disintegrins are a family of very potent plateletaggregation inhibitors isolated from venoms. These proteins interfere inthe interaction between fibrinogen and the glycoprotein IIb-IIIacomplex. The RGD sequence in disintegrins is located at the tip of aloop and is accessible for interaction. Several disintegrins and relatedinhibitors also contain proline residues.

The effectiveness of proline brackets was demonstrated by constructingseveral small RGD peptides. Small peptides containing the RGD sequenceinhibit adhesive reactions, including platelet aggregation. The sequenceIle-Ala-Arg-Gly-Asp-Met-Asn-Ala was selected as typical of peptidescontaining the Arg-Gly-Asp sequence. Proline residues were substitutedon one or both sides of the Arg-Gly-Asp-Met sequence. Four peptides,Ile-Ala-Arg-Gly-Asp-Met-Asn-Ala (P-1) (SEQ ID NO: 2),Ile-Pro-Arg-Gly-Asp-Met-Asn-Ala (P-2) (SEQ ID NO: 3),Ile-Ala-Arg-Gly-Asp-Met-Pro-Ala (P-3) (SEQ ID NO: 4), andIle-Pro-Arg-Gly-Asp-Met-Pro-Ala (P-4) (SEQ ID NO: 5), were synthesizedby solid phase peptide synthesis. After extraction, the peptides werepurified by a reverse phase HPLC system to more than 95% purity, withyields between 80% and 90%. The structures of individual peptides wereconfirmed by amino acid analysis, and their masses were confirmed byfast atom bombardment mass spectra.

The inhibition of platelet aggregation by these peptides was studied ina whole blood aggregometer. Platelet aggregations were initiated by theaddition either of collagen or of ADP. All four peptides inhibitedplatelet aggregation.

To compare the inhibitory potencies, the dose-response relationshipswere determined for the polypeptides, as identified below in Table 1.The inhibitory potencies of the polypeptides were P-4>P-3=P-2>P-1. Theconcentration of polypeptides inhibiting platelet aggregation by 50%("the IC₅₀ value") was determined from the dose-response curves; thefold-increase in the inhibitory potencies also was determined (Table 1).The inhibitory potency of Ile-Ala-Arg-Gly-Asp-Met-Asn-Ala is comparablewith that of the Arg-Gly-Asp-Ser peptide (SEQ ID NO: 6). Incorporationof proline on either side of Arg-Gly-Asp enhances the potency to aboutthe same extent. Inclusion of proline residues on both sides enhancedthe antiplatelet effect of the Arg-Gly-Asp peptide by 7 to 13-fold.

                  TABLE 1                                                         ______________________________________                                                     Donor 1        Donor 2                                           Peptide        IC50   Fold        IC50 Fold                                   ______________________________________                                        Collagen-induced aggregation                                                  P-1            84.5   --          67.3 --                                     P-2            48.8   1.73        27.6 2.44                                   P-3            37.5   2.25        27.6 2.44                                   P-4             6.4   13.10        8.4 8.01                                   Arg-Gly-Asp-Ser                                                                              57.8   --          32.3 --                                     ADP-induced aggregation                                                       P-1            27.3   --          22.5 --                                     P-2            21.5   1.27        18.9 1.19                                   P-3            21.0   1.30        16.7 1.34                                   P-4             4.0   6.77         2.2 10.27                                  Arg-Gly-Asp-Ser                                                                              29.9   --          13.8 --                                     ______________________________________                                         The inhibitory potency of P2, P3, and P4 were compared with P1 to obtain      the fold increase in its potency.                                        

There are other RGD-containing peptides that inhibit the interactionbetween fibrinogen and its platelet receptor, the glycoprotein IIb-IIIacomplex, and thus are platelet aggregation inhibitors. These peptidescan be administered by intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches or other appropriate means, usually in a dosage of100-2000 nM. Sequences include:

Ile-Pro-Arg-Gly-Asp-Tyr-Pro-Ala (PYP) (SEQ ID NO: 7)

Ile-Pro-Arg-Gly-Asp-Phe-Pro-Ala (PFP) (SEQ ID NO: 8)

Ile-Pro-Arg-Gly-Asp-Trp-Pro-Ala (PWP) (SEQ ID NO: 9)

Ile-Pro-Lys-Gly-Asp-Trp-Pro-Ala (PKWP) (SEQ ID NO: 10)

Ile-Pro-Homoarg-Gly-Asp-Trp-Pro-Ala (PhRWP) (SEQ ID NO: 11)

Each of these peptides have the generalized formula b-Pro-a-g-d-b orc-Pro-g based on the conservative substitution groups discussed above.

Another important interaction site on adhesive proteins is the sequenceLeu-Asp-Val (SEQ ID NO: 12 wherein proline brackets are provided to formthe sequence Ala-Pro-Leu-Asp-Val-Pro-Ala (SEQ ID NO: 13). Additionally,the interaction site having the sequence Val-Thr-Cys-Gly (SEQ ID NO: 14)can be bracketed providing the sequence Ala-Pro-Val-Thr-Cys-Gly-Pro-Ala(SEQ ID NO: 15).

These data demonstrate that the inclusion of conformation-constrainingmoieties can have desirable effects on an interaction site. These dataalso demonstrate that interaction sites possess activity when present ina polypeptide that differs from the native form. Finally, these datashow the propriety of identifying interaction sites by the presence ofproline brackets. Accordingly, the below-described analogs and homologsof the present invention, which contain conformation-constrainingbrackets like proline, have useful activities.

EXAMPLE II Truncated Analogs

The following sequences are obtained from naturally-occurringpolypeptides that contain proline brackets or proline/cysteine brackets.These polypeptides can be shortened to form fragments that contain oneor more interaction sites of interest. As stated above, these fragmentsare referred to as "truncated analogs."

The presence of the proline brackets is useful for identifying theinteraction sites of the polypeptides to permit construction of thetruncated analogs. The truncated analogs below can be employed in amanner similar to the naturally-occurring polypeptide. In this sense,the truncated analogs mimic the naturally-occurring polypeptide.

Hypotensive Peptides

Applications: Treatment of Cardiovascular Diseases by Reduction of BloodPressure

1. Origin Type: Calciseptine

Mechanism: Binds to L-type calcium channels in aorta and cardiacmyocytes and inhibits the calcium current. This helps in the relaxationof these muscles and thus reduces blood pressure.

Dose: 60 to 120 μg per rat (5 to 10 μM). Comparable to diltiazem (inCardizem-CD), which is on the market.

Advantages: Preliminary studies indicate that in the presence ofdiltiazem there is a small increase in the diastolic pressure. Thissuggests incomplete relaxation of the heart between beats when treatedwith diltiazem, which is detrimental. Treatment with the peptide,however, does not increase diastolic pressure. Also the peptide seems toexert anti-arrythmogenic activity.

Administration: Intravenous injections, inhalation, coated polymers(oral), implants, skin patches, and other appropriate means.

Structure:

Ala-Pro-Thr-Ala-Met-Trp-Pro-Ala (HP-1 or L-Calchin) (SEQ ID NO: 16)

2. Origin Type: Adrenomedulin

Mechanism: Reduces the blood pressure in rats through an unknownmechanism, possibly involving nerve terminals.

Dose: 30 to 100 μg/rat (30 to 100 nmole/rat)

Advantages: Increases cyclic AMP in platelets and may thus possessantiplatelet activity. Such antiplatelet activity is beneficial inreducing the risk of myocardial infarction and stroke in individualswith high blood pressure.

Administration: Intravenous injections, inhalation, coated polymers(oral), implants, skin patches and other appropriate means.

Structure:

Ala-Pro-Arg-Ser-Lys-Ile-Ser-Pro-Gln-Gly (HP-2 or Amulin) (SEQ ID NO: 17)

3. Origin Type: Maxadilan

Mechanism: Reduces blood pressure through vasodilation.

Dose: 200-500 nM (10 μg/rat).

Administration: Intravenous injections, inhalation, coated polymers(oral), implants and skin patches.

Structures:

Gln-Leu-Pro-Gly-Asn-Ser-Val-Phe-Lys-Glu-Pro-Met (HP-3 or Dilamax-1) (SEQID NO: 18)

Phe-Thr-Ser-Met-Asp-Thr-Ser-Gln-Leu-Pro-Gly (HP-4 or Dilamax-2) (SEQ IDNO: 19)

Fibrinolytic Peptides

Application: For dissolving clots formed in various thrombotic andhemostatic ailments including myocardial infarction and stroke.

Mechanism: Binds to plasminogen and non-proteolytically activatesplasminogen, which dissolves fibrin clot.

Dose: 1-300 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

1. Origin Type: Staphylokinase

Structures:

Ser-Pro-Arg-Tyr-Val-Glu-Phe-Pro-Ile-Lys-Pro-Gly (FP-STA1) (SEQ ID NO:20)

Phe-Pro-Ile-Thr-Glu-Lys-Gly-Phe-Val-Val-Pro-Asp (FP-STA2) (SEQ ID NO:21)

Val-Pro-Asp-Leu-Ser-Glu-His-Ile-Lys-Asn-Pro-Gly (FP-STA3) (SEQ ID NO:22)

Lys-Pro-Asp-Asp-Ala-Ser-Tyr-Phe-Glu-Pro-Thr-Gly-Pro-Tyr (FP-STA4) (SEQID NO: 23)

2. Origin Type: Streptokinase

Structures:

Arg-Pro-Tyr-Lys-Glu-Lys-Pro-Val (FP-SRP1) (SEQ ID NO: 24)

Thr-Pro-Leu-Asn-Pro-Asp-Asp-Asp-Phe-Arg-Pro-Gly (FP-SRP2) (SEQ ID NO:25)

Ser-Pro-Lys-Ser-Lys-Pro-Phe-Ala-Thr-Asp-Ser-Gly-Ala-Met-Pro-His(FP-SRP3) (SEQ ID NO: 26)

Chemotactic Peptides

Applications: Attract neutrophils and macrophages and hence will beuseful in enhancing body defense mechanism at a required site.

Mechanism: Probably through specific receptor interaction.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

1. Origin Type: CP-10

Dose: 10-100 pM

Structure:

Ala-Pro-Gln-Phe-Val-Gln-Asn-Ile-Pro-Ala (CP-CP10A) (SEQ ID NO: 27)

2. Origin Type: Interleukin-8

Dose: 5-100 nM

Structure:

Lys-Glu-Leu-Arg-Pro-Gln (CP-IL8A) (SEQ ID NO: 28)

Origin Type: α-1 Proteinase Inhibitor

Dose: 5-100 nM

Structures:

Ala-Pro-Glu-Val-Lys-Phe-Asn-Lys-Pro-Phe-Val (CP-αPI1) (SEQ ID NO: 29)

Ser-Pro-Leu-Phe-Ile-Gly-Lys-Val-Val-Asn-Pro-Thr (CP-αPI2) (SEQ ID NO:30)

Growth Promoter Peptides

Neurite-Promoting Peptides

Applications: In treatment of injuries to nervous system and trauma.Helpful in promoting growth of neurites to regenerate broken connectionscaused by injury.

1. Origin Type: Pleiotrophin

Mechanism: Through interaction with specific receptors.

Dose: 50 to 200 nM.

Advantages: Smaller size of the peptide may help the molecule cross theblood-brain barrier.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Ser-Lys-Pro-Ala-Gly-Lys-Leu-Thr-Lys-Ser-Lys-Pro-Gln-Ala (NPP-PT1) (SEQID NO: 31)

Ser-Lys-Pro-Ala-Gly-Lys-Leu-Thr-Lys-Pro-Lys-Pro-Gln-Ala (NPP-PT2) (SEQID NO: 32)

Lys-Ile-Pro-Ala-Asn-Trp-Lys-Lys-Gln-Phe-Pro-Ala (NPP-PT3) (SEQ ID NO:33)

Homology: The NPP-PT1 and NPP-PT2 polypeptides have the generalizedformula (SEQ ID NO: 148) f-a-Pro-g-g-a-b-f-a based on the conservativesubstitution groups discussed above.

2. Origin Type: Ciliary Neurotrophic Factor

Mechanism: Probably through specific receptors.

Dose: 5-200 nM.

Advantages: Smaller size of the peptide may help the molecule cross theblood-brain barrier.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and othersuitable means.

Structures:

Val-Pro-Val-Ala-Ser-Thr-Asp-Arg-Trp-Ser-Glu-Leu-Thr-Glu-Ala (NPP-CNTF1)(SEQ ID NO: 34)

Ile-Pro-Arg-Asn-Glu-Ala-Asp-Gly-Met-Pro-Ile (NPP-CNTF2) (SEQ ID NO: 35)

Granulocyte Colony Stimulating Peptides

Applications: Helpful in proliferation and differentiation ofhemopoietic precursors and stimulation of mature cells. For treatment ofneutropenia in a variety of clinical situations.

Mechanism: Through interaction with specific receptors.

Dose: 50 to 200 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

1. Origin Type: GCSP

Structures:

Ala-Pro-Ser-Gln-Ala-Leu-Gln-Leu-Ala-Pro-Ala (GCSP-1) (SEQ ID NO: 36)

Ala-Pro-Ala-Leu-Gln-Pro-Thr-Gln-Gly-Ala-Met-Pro-Ala (GCSP-2) (SEQ ID NO:37)

Ile-Pro-Trp-Ala-Pro-Leu-Ser-Ser-Ala-Pro-Ser (GCSP-3) (SEQ ID NO: 38)

Ser-Pro-Glu-Leu-Gly-Pro-Thr-Leu (GCSP-4) (SEQ ID NO: 39)

Thr-Pro-Leu-Gly-Pro-Ala-Ser-Ser-Leu-Pro-Gln-Ser (GCSP-5) (SEQ ID NO: 40)

2. Origin Type: IL-3

Structure:

Leu-Pro-Leu-Ala-Thr-Ala-Ala-Pro-Thr-Arg-His-Pro-Ile (IL3A) (SEQ ID NO:41)

Progen (SCF Peptides)

Applications: Helpful in proliferation and differentiation ofhemopoietic precursors and stimulation of mature cells. For treatmentafter bone marrow transplants and various other clinical situations.

Origin Type: Stem Cell Factor

Mechanism: Interact with specific receptors and enhance the growth anddifferentiation of progenitor cells.

Dose: 100 to 500 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and othersuitable means.

Structures:

Asp-Pro-Val-Val-Ser-Ser-Thr-Leu-Ser-Pro-Glu (SCF-1; Progen-1) (SEQ IDNO: 42)

Val-Pro-Gly-Met-Asp-Val-Leu-Pro-Ser (SCF-2; Progen-2) (SEQ ID NO: 43)

Ser-Pro-Glu-Pro-Arg-Leu-Phe-Thr-Pro-Glu (SCF-3; Progen-3) (SEQ ID NO:44)

Endothelial Growth Peptides

Applications: For inducing growth of vasculature. Helpful in woundhealing after surgical procedures as well as in severe damage caused byaccidents.

Origin Type: Vascular Permeability Factor

Dose: 50 to 300 nM.

Administration: Intravenous injections, in situ injections, topicalapplication, inhalation, oral administration using coated polymers,dermal patches or other suitable means.

Structure:

Tyr-Pro-Asp-Glu-Ile-Glu-Tyr-Ile-Phe-Lys-Pro-Ser (VPF-1) (SEQ ID NO: 45)

Neurotrophic Factor

Applications: For treatment of injuries and trauma to the nervoussystem. Helpful in promoting growth of neurites to regenerate brokenconnections caused by injury.

Origin Type: Glial Cell Line-Derived Neurotrophic Factor

Mechanism: Promotes the growth of dopaminergic neurons throughinteraction with specific receptors.

Dose: 50 to 200 nM.

Advantages: The small size of the peptide may help the molecule crossthe blood-brain barrier.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Ser-Pro-Asp-Lys-Gln-Ala-Ala-Ala-Leu-Pro-Arg-Arg (NPP-GDNF1) (SEQ ID NO:46)

Asn-Pro-Glu-Asn-Ser-Arg-Pro-Lys (NPP-GDNF2) (SEQ ID NO: 47)

Lymphocyte Mitogens

Origin Tore: Streptococcus pyrogenes Mitogenic Factor

Dose: 1 to 100 μM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Thr-Pro-Ala-Leu-Phe-Pro-Lys (LM-SP1) (SEQ ID NO: 48)

Asn-Pro-Ala-Gly-Trp-Thr-Gly-Asn-Pro-Asn (LM-SP2) (SEQ ID NO: 49)

Ala-Pro-Ile-Tyr-Asn-Ala-Asp-Glu-Leu-Ile-Pro-Arg (LM-SP3) (SEQ ID NO: 50)

Immunomodulator Peptides

1. Origin Type: Ling-Zhi-8

Applications: Combating several inflammatory autoimmune diseases andothers. Antidiabetic and antitumor effects.

Mechanism: Activate T-cells and facilitate cellular interaction.

Dose: 10-150 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Tyr-Thr-Pro-Asn-Trp-Gly-Arg-Gly-Asn-Pro-Asn-Asn (IP-LZ1) (SEQ ID NO: 51)

Gly-Asn-Pro-Asn-Asn-Phe-Ile-Asp-Thr-Val-Thr-Phe-Pro-Lys-Val (IP-LZ2)(SEQ ID NO: 52)

2. Origin Type: IL-4

Mechanism: Bind to specific receptors and inhibit cell-mediatedimmunity, enhances humoral immunity.

Dose: 10-500 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Leu-Pro-Val-Thr-Asp-Ile-Phe-Ala-Ala-Pro-Lys (IP-IL4A) (SEQ ID NO: 53)

Ala-Pro-Val-Lys-Glu-Ala-Asn-Gln-Pro-Thr (IP-IL4B) (SEQ ID NO: 54)

Thr-Pro-Ala-Thr-Glu-Leu-Thr-Val-Pro-Asp (IP-IL4C) (SEQ ID NO: 55)

Ser-Pro-His-Glu-Lys-Asp-Thr-Arg-Pro-Leu (IP-IL4D) (SEQ ID NO: 56)

3. Origin Type: IL-10

Mechanism: Bind to specific receptors and inhibit cell-mediatedimmunity, enhances humoral immunity.

Dose: 10-500 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Val-Pro-Gln-Ala-Glu-Asn-Gln-Asp-Pro-Asp-Ile (IP-IL10A) (SEQ ID NO: 57)

Arg-Pro-His-Arg-Phe-Leu-Pro-Ala (IP-IL10B) (SEQ ID NO: 58)

His-Phe-Pro-Gly-Asn-Leu-Pro-Asn-Met-Leu (IP-IL10C) (SEQ ID NO: 59)

Clot-inducing Peptides

Applications: Effective in controlling blood loss in various situations,including surgical procedures and accidents.

1. Origin Type: Staphylocoagulase

Mechanism: Bind and non-proteolytically activate prothrombin which inturn induces blood clotting.

Dose: 1-200 μM.

Administration: Topical applications by spraying at the site of thedamage.

Structures:

Thr-Pro-Ala-Ile-Asp-Leu-Leu-Glu-Thr-Tyr-Lys-Tyr-Gly-Asp-Pro-Ile(CIP-STA1) (SEQ ID NO: 60)

Asp-Pro-Ile-Tyr-Lys-Glu-Ala-Lys-Asp-Arg-Leu-Met-Thr-Arg (CIP-STA2) (SEQID NO: 61)

Asn-Pro-His-Lys-Ile-Thr-Asn-Glu-Arg-Ile-Lys (CIP-STA3) (SEQ ID NO: 62)

Glu-Leu-Arg-Ala-Lys-Leu-Asp-Leu-Ile-Leu-Pro-Asp (CIP-STA4) (SEQ ID NO:63)

Ser-Pro-Val-Val-Lys-Glu-Glu-Asn-Lys-Val-Glu-Glu-Pro-Gln-Leu (CIP-STA5)(SEQ ID NO: 64)

2. Origin Type: Botrocetin

Mechanism: Interact with von Willebrand factor and/or glycoprotein Iband induce platelet aggregation.

Dose: 1-200 μM.

Applications: Effective in controlling blood loss in various situations,including surgical procedures and accidents.

Administration: Topical applications by spraying at the site of thedamage.

Structures:

Lys-Pro-Thr-Asn-Asn-Lys-Trp-Trp-Ile-Ile-Pro-Ala (CIP-BCTN1) (SEQ ID NO:65)

Ala-Pro-Ser-Gly-Trp-Ser-Ser-Tyr-Glu-Gly-Asn-Pro-Tyr (CIP-BCTN2) (SEQ IDNO: 66)

Asn-Pro-Phe-Val-Ala-Lys-Ser-Pro-Ala (CIP-BCTN3) (SEQ ID NO: 67)

Cardiac Stimulant Peptides

Origin Type: Anthopleurin A and B

Mechanism: Bind to voltage-gated sodium channels and prolong the actionpotential, which causes cardiostimulatory effects.

Dose: 50-1000 nM.

Administration: Intravenous injections, inhalation, oral administrationusing coated polymers, dermal patches and other appropriate means.

Structures:

Arg-Pro-Arg-Gly-Asn-Thr-Leu-Ser-Pro-Ala (CSP-APB1) (SEQ ID NO: 68)

Gly-Pro-Ser-Val-Arg-Gly-Asn-Thr-Leu-Ser-Pro-Ala (CSP-APA1; Aleurin) (SEQID NO: 69)

Homology: The CSP-APA1 and CSP-APB1 polypeptides have the generalizedformula (SEQ ID NO: 149) a-g-e-f-b-f-Pro-g based on the conservativesubstitution groups discussed above.

Sweet Peptides

Applications: As non-nutrient sweeteners for food, drink, desserts,candies, chewing gums and medicine. Helpful in both normal and lowcalorie diets for reducing calorie intake. Useful in making bittermedicine and pills more palatable. Suitable for persons with diabetes.

Mechanism: These peptides bind to receptors of sweet tasting papillaeand induce a sweet sensation.

Dose: Typically, these peptides are 5000 to 10,000 times sweeter thansugar. In comparison, aspartame is only 160 times sweeter than sugar.

Administration: Oral

Modifications: Other structural constraints, particularly cyclization,may improve the heat stability of these peptides. Stabilization shouldincrease the usefulness of these polypeptides in cooking.

1. Origin Type: Thaumatin

Structures:

Ala-Pro-Ala-Lys-Leu-Lys-Ala-Pro-Gly (SW-T1) (SEQ ID NO: 70)

Ala-Pro-Gly-Ser-Ser-Asn-Tyr-Arg-Val-Thr-Phe-Ala-Pro-Thr-Ala (SW-T2) (SEQID NO: 71)

Gly-Pro-Thr-Glu-Tyr-Ser-Arg-Phe-Phe-Lys-Arg-Leu-Ala-Pro-Asp (SW-T3) (SEQID NO: 72)

Asp-Lys-Pro-Thr-Thr-Val-Thr-Ala-Pro-Gly (SW-T4) (SEQ ID NO: 73)

Asn-Val-Pro-Met-Asn-Phe-Ser-Pro-Thr-Thr (SW-T5) (SEQ ID NO: 74)

2. Origin Type: Monellin

Structures:

Ile-Arg-Pro-Ala-Met-Lys-Lys-Thr-Ile-Tyr-Glu-Asn-Glu (SW-M1) (SEQ ID NO:75)

Arg-Pro-Arg-Lys-Leu-Leu-Arg-Phe-Asn-Gly-Pro-Val (SW-M2) (SEQ ID NO: 76)

3. Origin Type: Mabinlin

Structures:

Gln-Pro-Arg-Arg-Pro-Ala-Leu-Arg-Gln-Pro-Ala (SW-MB1) (SEQ ID NO: 77)

Ala-Pro-Asn-Gln-Leu-Arg-Gln-Val-Asp-Arg-Pro-Ala (SW-MB2) (SEQ ID NO: 78)

Ile-Pro-Asn-Ile-Gly-Ala-Ala-Pro-Phe-Arg-Ala-Trp (SW-MB3) (SEQ ID NO: 79)

Ile-His-Arg-Arg-Ala-Gln-Phe-Gly-Gly-Gln-Pro-Asp (SW-MB4) (SEQ ID NO: 80)

Leu-Pro-Asn-Ile-Ala-Asn-Ile-Pro-Asn (SW-MB5) (SEQ ID NO: 81)

Taste-Modifier Peptides

Applications: As modifiers of sour taste into sweet taste.

Mechanism: Probably through interaction with taste receptors.

Dose: 30 nM to 500 nM.

Administration: Oral.

Modifications: Structural constraints, particularly cyclization of thepeptides, may help in the heat stability of these peptides.Stabilization should increase the usefulness of these polypeptides incooking.

1. Origin Type: Miraculin

Structures:

Asp-Arg-Pro-Leu-Ala-Phe-Phe-Pro-Glu-Asn-Pro-Lys-Glu (TM-MIR1) (SEQ IDNO: 82)

Thr-Thr-Pro-Asn-Gly-Thr-Phe-Val-Ala-Pro-Arg-Val (TM-MIR2) (SEQ ID NO:83)

2. Origin Type: Curculin

Structure:

Tyr-Gly-Pro-Val-Leu-Trp-Ser-Leu-Gly-Pro-Asn-Gly (TM-CUR1) (SEQ ID NO:84)

Macrophage Activating Peptide

Origin Type: Interferon gamma

Applications: The following peptide should activate macrophages fortumor cytotoxicity and to kill parasites. It should be useful intreatment of malaria and other parasitic diseases.

Mechanism: Bind to specific receptors on macrophage surface.

Dose: 10-500 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structure: Ser-Pro-Ala-Ala-Lys-Thr-Pro-Lys-Arg (IFNG1) (SEQ ID NO: 85)

Anti-contraction Peptides

Application: To prevent premature labor in pregnant women.

Origin Type: Relaxin

Mechanism: Bind to relaxin receptors and induce uterine relaxation.

Dose: 1-20 nmole/mouse

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Leu-Pro-Gly-Arg-Glu-Leu-Val-Arg-Ala-Gln-Ile-Ala-Ile-Pro-Gly (ACP-R1)(SEQ ID NO: 86)

Leu-Pro-Gly-Arg-Glu-Leu-Val-Arg-Ala-Val-Ile-Gln-Ile-Pro-Gly (ACP-RA)(SEQ ID NO: 87)

Homology: The ACP-R1 and ACP-RA polypeptides have the generalizedformula (SEQ ID NO: 150) b-Pro-g-a-d-b-b-a-g based on the conservativesubstitution groups discussed above.

Antitumor Peptides

Mechanism: Interact with specific receptors and inhibit tumor growth.

Dose: 0.5-10 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches or othersuitable means.

1. Origin Type: Oncostatin M

Structures:

Asp-Pro-Tyr-Ile-Arg-Ile-Gln-Gly-Leu-Asp-Val-Pro-Lys-Leu (ATP-OSM1) (SEQID NO: 88)

Glu-Arg-Pro-Gly-Ala-Phe-Pro-Ser-Glu (ATP-OSM2) (SEQ ID NO: 89)

Glu-Pro-Thr-Lys-Ala-Gly-Arg-Gly-Ala-Ser-Gln-Pro-Ala (ATP-OSM3) (SEQ IDNO: 90)

2. Origin Type: Leukemia Inhibitory Factor

Structures:

Thr-Pro-Val-Asn-Ala-Thr-Pro-Ala (ATP-LIF1) (SEQ ID NO: 91)

Thr-Pro-Ala-Ile-Arg-His-Pro-Ala (ATP-LIF2) (SEQ ID NO: 92)

Phe-Pro-Asn-Asn-Leu-Asp-Lys-Leu-Pro-Gly (ATP-LIF3) (SEQ ID NO: 93)

Gly-Pro-Asn-Val-Thr-Asp-Phe-Pro-Ser (ATP-LIF4) (SEQ ID NO: 94)

Antiplatelet Peptides

1. Origin Type: Leech Antiplatelet Protein

Mechanism: Interacts with collagen receptor and inhibitscollagen-induced platelet aggregation.

Dose: 1-4 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches.

Structures:

Lys-Arg-Pro-Gly-Trp-Lys-Leu-Pro-Asp-Asn (APCol-1) (SEQ ID NO: 95)

Met-Pro-Glu-Glu-Ser-Ala-Val-Glu-Pro-Ser (APCol-2) (SEQ ID NO: 96)

2. Origin Type: Moubatin

Mechanism: Interacts with collagen receptor and inhibitscollagen-induced platelet aggregation.

Dose: 1-4 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches or other appropriate means.

Structures:

Asp-Pro-Gln-Ala-Arg-Asp-Pro-Leu-Lys-Gly-Thr-Pro-Asn (APCol-M1) (SEQ IDNO: 97)

Thr-Pro-Asn-Gly-Asn-Arg-Asp-Gly-Asn-Thr-Leu-Pro-Val (APCol-M2) (SEQ IDNO: 98)

Anti-fibrinogen Peptides

Origin Type: Monoclonal Antibody against the Fibrinogen α chain

Mechanism: Interferes with fibrin polymerization Dose: 1-2 mM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

Structure:

His-Pro-Gly-Ile-Ala-Glu-Phe-Pro-Ser-Arg-Ala (AC-9E9) (SEQ ID NO: 99)

Alzheimer's Disease--HGIF

Applications: The brain of Alzheimer's disease patients contains reducedamounts of a growth inhibitory factor (GIF) which is abundant in normalhuman brain. This may account for the increased neurotrophic activity,leading to massive sprouting of cortical neurons, cell exhaustion anddeath. The following peptide should replace GIF and hence prevent thedevelopment of the disease.

Origin Type: Human Growth Inhibitory Factor

Dose: 1-5000 nM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

Structure:

Ala-Pro-Ser-Gly-Gly-Ser-Pro-Thr (ADP-GIF1) (SEQ ID NO: 100)

EXAMPLE III Truncated Analogs as Antagonists or Inhibitors

The following analogs can function as antagonists or inhibitors ofnatural polypeptides by binding to the natural polypeptide or bycompeting with the natural polypeptides for their interactionpartner(s). These analogs are shorter than their natural counterpartsand, thus, are truncated analogs.

Antifertility Peptides

Applications: In population control as a reversible antifertilitymeasure.

Origin Type: LHRH Receptor

Dose: 5-5000 μM

Mechanism: Bind to gonadotropin releasing hormone and thus interferewith the fertility of men and women.

Administration: Intravenous injections, inhalation, oral administrationusing coated polymers, dermal patches and other appropriate means.

Structures:

Ile-Pro-Leu-Met-Gln-Gly-Asn-Leu-Pro-Thr (AFP-LHRHR1) (SEQ ID NO: 101)

Asp-Pro-Glu-Met-Leu-Asn-Arg-Leu-Ser-Asp-Pro-Val (AFP-LHRHR2) (SEQ ID NO:102)

Leu-Pro-Thr-Leu-Thr-Leu-Ser-Pro-Lys (AFP-LHRHR3) (SEQ ID NO: 103)

Anti-contraction Peptides

Application: To prevent premature labor in pregnant women.

Origin Type: Angiotensin II Receptor (type 1)

Mechanism: Interact with angiotensin II and abrogate its ability toinduce contraction.

Dose: 1-200 μM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Asp-Pro-Ile-Lys-Arg-Ile-Gln-Asp-Asp-Ala-Pro-Lys-Ala (ACP-AT1RA) (SEQ IDNO: 104)

Val-Pro-Ala-Phe-His-Tyr-Glu-Ser-Gln-Asn-Ser-Thr-Leu-Pro-Ile (ACP-AT1RB)(SEQ ID NO: 105)

Trp-Pro-Phe-Gly-Asn-Val-Leu-Pro-Lys (ACP-AT1RC) (SEQ ID NO: 106)

Anti-inflammatory Peptides

1. Origin Type: Interleukin-8 Receptor

Mechanism: Bind to interleukin-8 and inhibit its ability to act as achemo-attractant, and thus abrogate the pro-inflammatory effects of theinterleukin.

Dose: 5-50 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Leu-Pro-Pro-Phe-Leu-Leu-Asp-Ala-Ala-Pro-Ala (AIP-IL8R1) (SEQ ID NO: 107)

Glu-Pro-Glu-Ser-Leu-Glu-Ile-Asn-Lys-Pro-Tyr (AIP-IL8R2) (SEQ ID NO: 108)

2. Origin Type: Macrophage Migration Inhibitors

Mechanism: Interacts with specific receptors and inhibits the migrationof macrophages, thus stopping pro-inflammatory response.

Dose: 5-100 nM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structure:

Lys-Pro-Pro-Gln-Tyr-Ile-Ala-Val-His-Val-Val-Pro-Asp-Gln (AIP-MIF1) (SEQID NO: 109)

3. Origin Type: Fibrinogen γ-chain

Mechanism: Inhibits the interactions between fibrinogen and itsleukocyte receptor CD11b/CD18 integrin (Mac-1).

Dose: 0.8-20 μM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structure:

Asn-Pro-Trp-Thr-Val-Phe-Gln-Lys-Arg-Leu-Asp-Pro-Ser-Val (AIP-FBG1) (SEQID NO: 110)

Platelet Derived Growth Factor Inhibitors

Origin Type: Platelet-Derived Growth Factor

Mechanism: Blocks binding of platelet-derived growth factor (PDGF) toits receptor, which blocks the effects of PDGF on smooth muscle.

Dose: 5-5000 μM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration using coated polymers, dermal patches and otherappropriate means.

Structures:

Pro-Ser-Gly-Ser-Ala-Pro (PGF-1) (SEQ ID NO: 111)

Pro-Arg-Val-Thr-Asp-Pro (PGF-2) (SEQ ID NO: 112)

Pro-Arg-Gly-Arg-Gly-Met-Pro-Gln-Pro (PGF-3) (SEQ ID NO: 113)

Blood Protein Inhibitors and Antagonists

1. Origin Type: Factor V

Structures:

Glu-Met-Lys-Ala-Ser-Lys-Pro-Gly-Trp-Trp-Leu (AC-5A1) (SEQ ID NO: 114)

Leu-Pro-Gly-Ser-Phe-Lys-Thr-Leu-Glu-Met-Lys-Ala-Ser-Lys-Pro-Gly (AC-5A2)(SEQ ID NO: 115)

Mechanism: Interferes with the generation of thrombin from prothrombin.

Dose: 1-2 mM

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

2. Origin Type: Factor VIII

Mechanism: Interferes with the activation of factor X

Dose: 1-2 mM

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

Structures:

Glu-Met-Leu-Pro-Ser-Lys-Ala-Gly-Ile-Trp-Arg (AC-8A1) (SEQ ID NO: 116)

Tyr-Pro-Gly-Val-Phe-Glu-Thr-Val-Glu-Met-Leu-Pro-Ser (AC-8A2) (SEQ ID NO:117)

3. Origin Type: Naja nigricollis Phospholipase CM-IV

Mechanism: Interferes with coagulation

Dose: 1-2 mM

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

Structures:

Tyr-Glu-Lys-Ala-Gly-Lys-Met-Gly-Ala-Trp-Pro-Tyr (AC-PL1) (SEQ ID NO:118)

Trp-Pro-Tyr-Leu-Thr-Leu-Tyr-Lys-Tyr-Lys-Ala-Ser-Ala (AC-PL2) (SEQ ID NO:119)

4. Origin Type: Prothrombin

Mechanism: The native polypeptide, also known as factor II, is theprecursor of thrombin. The truncated analog binds with factors thatwould otherwise generate thrombin from prothrombin.

Dose: 50-5000 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

Structures:

Ser-Pro-Trp-Gln-Val-Met-Leu-Phe-Arg-Lys-Ser-Pro-Gln-Glu-Leu-Leu-Pro-Gly(ACS-THR1) (SEQ ID NO: 120)

Leu-Pro-Arg-Lys-Ser-Pro-Gln-Glu-Leu-Leu-Pro-Gly (ACS-THR2) (SEQ ID NO:121)

Ile-Pro-Lys-His-Ser-Arg-Thr-Arg-Tyr-Pro-Arg-Asn-Ile-Glu-Lys (ACS-THR3)(SEQ ID NO: 122)

Homology: The ACS-THR1 and ACS-THR2 polypeptides have the generalizedformula (SEQ ID NO: 151) a-a-f-Pro-e-d-b-b-Pro-g based on theconservative substitution groups discussed above.

5. Origin Type: Factor Xa

Mechanism: Interferes in the generation of thrombin from prothrombin.

Dose: 50-5000 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches or other appropriate means.

Structures:

Ala-Pro-Trp-Gln-Ala-Leu-Leu-Ile-Asn-Glu-Glu-Asn-Glu-Gly-Phe-Pro-Gly(ACS-Xa1) (SEQ ID NO: 123)

Leu-Pro-Asn-Glu-Glu-Asn-Glu-Gly-Phe-Pro-Gly (ACS-Xa2) (SEQ ID NO: 124)

Leu-Pro-Asn-Glu-Clu-Asn-Glu-Pro-Phe (ACS-Xa3) (SEQ ID NO: 125)

Val-Pro-Asp-Arg-Asn-Thr-Glu-Gln-Glu-Glu-Pro-Gly (ACS-Xa4) (SEQ ID NO:126)

Homology: The ACS-Xa2 and ACS-Xa3 polypeptides have the generalizedformula (SEQ ID NO: 152) b-Pro-e-d-d-e-d based on the conservativesubstitution groups discussed above.

6. Origin Type: Factor IXa

Mechanism: Interferes with the activation of factor X

Dose: 50-5000 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

Structure:

Phe-Pro-Trp-Gln-Val-Val-Leu-Asn-Gly-Lys-Val-Asp-Ala-Phe-Pro-Gly(ACS-IXa1) (SEQ ID NO: 127)

Asn-Pro-Lys-Val-Asp-Ala-Phe-Pro-Gly (ACS-IXa2) (SEQ ID NO: 128)

Ala-Pro-Glu-His-Asn-Ile-Glu-Glu-Thr-Glu-His-Thr-Glu-Pro-Lys (ACS-IXa3)(SEQ ID NO: 129)

7. Origin Type: Factor VIIa

Mechanism: Interferes with the activation of factor X

Dose: 50-5000 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

Structures:

Ala-Pro-Trp-Gln-Val-Leu-Leu-Leu-Val-Asn-Gly-Ala-Gln-Leu-Pro-Gly(ACS-VIIa1) (SEQ ID NO: 130)

Ala-Pro-Trp-Gln-Val-Leu-Leu-Leu-Val-Asn-Pro-Ala-Gln-Leu-Pro-Gly(ACS-VIIa2) (SEQ ID NO: 131)

Leu-Pro-Glu-His-Asp-Leu-Ser-Glu-His-Asp-Pro-Asp (ACS-VIIa3) (SEQ ID NO:132)

Homology: The ACS-VIIa1 and ACS-VIIa2 polypeptides have the generalizedformula (SEQ ID NO: 153) g-Pro-c-e-b-b-b-b-b-e based on the conservativesubstitution groups discussed above.

Antiplatelet Peptides

Several blood proteins are useful for their antiplatelet properties. Theproteins can be used as antithrombotic drugs for the prevention andtreatment of myocardial infarction, stroke and other related disorders.These proteins may have significant antitumor effects, as well as beinguseful for wound healing.

1. Origin Type: von Willebrand Factor

Structure: Ala-Pro-Leu-His-Asp-Phe-Tyr-Pro-Ser (AAP-VWF1) (SEQ ID NO:133)

Mechanism: Interferes in the interaction between von willebrand factorand glycoprotein Ib and thus inhibits platelet agglutination.

Dose: 10-50 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

2. Origin Type: Platelet Glycoprotein IIb

Structure: Gln-Pro-Asn-Asp-Gly-Gln-Pro-His (AAP-GPIIb1) (SEQ ID NO: 134)

Mechanism: Interferes in the interaction of glycoprotein IIb withadhesive ligands.

Dose: 5-100 μM.

Administration: Intravenous injections, in situ injections, localapplications, inhalation, oral administration using coated polymers,dermal patches and other appropriate means.

EXAMPLE IV Homologs

Polypeptide homologs can be based upon biologically active polypeptides,such as naturally-occurring polypeptides or polypeptides derivedtherefrom, which do not contain conformation-constraining moieties, suchas proline, around interaction sites. Such polypeptides can be alteredby inserting conformation-constraining moieties into the polypeptide sothat these moieties bracket the interaction site.

Homologs of polypeptides that already contain conformation-constrainingbrackets also can be made, according to the present invention, byaltering the location or structure of the bracket. For instance, anaturally-occurring proline residue that is within five amino acids ofan interaction site can be moved to be within two amino acids of theinteraction site. Additionally, a cyclic constraining moiety can besubstituted with a proline to alter the properties of the interactionsite. Furthermore, as stated above a homolog can also be shortened sothat its length is less than that of the native polypeptide. These andother changes will become apparent in view of the teachings of thisapplication.

Like the analogs, homologs can mimic the activity of the nativepolypeptide or serve as antagonists. The non-limiting examples belowinclude mimicking and antagonizing homologs. The sequences of the nativepolypeptides are known.

Analgesics

Origin Type: Enkephalins

Application: Alleviation of pain and emotional stress.

Dose: 5-5000 μM.

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Structures:

Pro-Tyr-Gly-Gly-Phe-Met-Pro (AN-1) (SEQ ID NO: 135)

Pro-Tyr-Gly-Gly-Phe-Leu-Pro (AN-2) (SEQ ID NO: 136)

Appetite Suppressant

Origin Type: Cholecystokinin

Application: Suppression of appetite.

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

Structure:

Pro-Phe(4-tetrazole)-Met-Gly-Trp-Met-Asp-Phe-Pro (AS-1) (SEQ ID NO: 137)

B-Cell Differentiating Peptide

Origin Type: B-Cell Differentiating Peptide

Application: Treatment of immune disorders resulting from low levels ofgamma globulin

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

Structure:

Pro-Lys-His-Gly-Pro (BCD-1) (SEQ ID NO: 138)

Hypocalcemic Agent

Origin Type: Calcitonin

Application: Mimics human calcitonin. Lowers blood calcium and phosphatelevels, and prevents demineralization of bones.

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

Structure:

a Pro-Gln-Thr-Ala-Ile-Gly-Val-Gly-Ala-Pro (HCA-1) (SEQ ID NO: 139)

Hypoglycemic Potentiator

Origin Type: Human Growth Hormone

Application: Useful for lowering the effective dosages of insulin.

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

Structure:

Pro-Glu-Glu-Ala-Tyr-Ile-Pro-Lys (HGP-1) (SEQ ID NO: 140)

Hypotensive Agent

Origin Type: Prolyl-phenylalanyl-arginine chains

Application: Reduction of blood pressure by reducing kidney vesselresistance.

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

Structure:

Pro-Pro-Phe-Arg-Pro (HTA-1) (SEQ ID NO: 141)

Immune Potentiator

Application: Stimulates differentiation of stem cells intothymus-derived cells and antibody production.

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

1. Origin Type: Thymopoietin

Structure:

Arg-Pro-Asp-Gly-Trp-Pro (IP-1) (SEQ ID NO: 142)

2. Origin Type: Thymosin α1

Structure:

Pro-Val-Glu-Glu-Ala-Glu-Asn-Pro (IP-2) (SEQ ID NO: 143)

Somatostatin-Like Peptide

Origin Type: Somatostatin

Application: To inhibit oversecretion of glucagon and/or growth hormonein conditions such as acromegaly and diabetes.

Administration: Intravenous injections, in situ injections. inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

Structure:

Pro-Lys-Asn-Phe-Phe-Trp-Lys-Thr-Phe-Thr-Pro (SLP-1) (SEQ ID NO: 144)

Gastrin-Releasing Peptide Antagonists

Origin Type: Gastrin Releasing Peptide

Application: Inhibits the action of gastrin-releasing peptide. Can beused for treatment of small cell lung carcinoma by prevention of thegrowth-promoting action of gastrin-releasing peptide.

Administration: Intravenous injections, in situ injections, inhalation,oral administration with coated polymers, dermal patches, and otherappropriate means.

Dose: 5-5000 μM.

Structure:

Pro-His-Trp-Ala-Val-Gly-His-Leu-Pro (GRP-1) (SEQ ID NO: 145)

The foregoing description, specific examples and data, while indicatingpreferred embodiments, are given by way of illustration and are notintended to limit the present invention. Various changes andmodifications within the present invention will be apparent to theskilled artisan from the discussion and disclosure contained herein.

    __________________________________________________________________________    #             SEQUENCE LISTING                                                - (1) GENERAL INFORMATION:                                                    -    (iii) NUMBER OF SEQUENCES: 153                                           - (2) INFORMATION FOR SEQ ID NO:1:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 3 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:1:                                 - Arg Gly Asp                                                                 - (2) INFORMATION FOR SEQ ID NO:2:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:2:                                 - Ile Ala Arg Gly Asp Met Asn Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:3:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:3:                                 - Ile Pro Arg Gly Asp Met Asn Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:4:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:4:                                 - Ile Ala Arg Gly Asp Met Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:5:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:5:                                 - Ile Pro Arg Gly Asp Met Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:6:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:6:                                 - Arg Gly Asp Ser                                                             1                                                                             - (2) INFORMATION FOR SEQ ID NO:7:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:7:                                 - Ile Pro Arg Gly Asp Tyr Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:8:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:8:                                 - Ile Pro Arg Gly Asp Phe Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:9:                                            -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:9:                                 - Ile Pro Arg Gly Asp Trp Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:10:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:10:                                - Ile Pro Lys Gly Asp Trp Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:11:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Arg at position 3ATION:                                              #homoarginine" represents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:11:                                - Ile Pro Arg Gly Asp Trp Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:12:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 3 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:12:                                - Leu Asp Val                                                                 1                                                                             - (2) INFORMATION FOR SEQ ID NO:13:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:13:                                - Ala Pro Leu Asp Val Pro Ala                                                 1               5                                                             - (2) INFORMATION FOR SEQ ID NO:14:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 4 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:14:                                - Val Thr Cys Gly                                                             1                                                                             - (2) INFORMATION FOR SEQ ID NO:15:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:15:                                - Ala Pro Val Thr Cys Gly Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:16:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:16:                                - Ala Pro Thr Ala Met Trp Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:17:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:17:                                - Ala Pro Arg Ser Lys Ile Ser Pro Gln Gly                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:18:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:18:                                - Gln Leu Pro Gly Asn Ser Val Phe Lys Glu Pr - #o Met                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:19:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:19:                                - Phe Thr Ser Met Asp Thr Ser Gln Leu Pro Gl - #y                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:20:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:20:                                - Ser Pro Arg Tyr Val Glu Phe Pro Ile Lys Pr - #o Gly                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:21:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:21:                                - Phe Pro Ile Thr Glu Lys Gly Phe Val Val Pr - #o Asp                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:22:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:22:                                - Val Pro Asp Leu Ser Glu His Ile Lys Asn Pr - #o Gly                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:23:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:23:                                - Lys Pro Asp Asp Ala Ser Tyr Phe Glu Pro Th - #r Gly Pro Tyr                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:24:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:24:                                - Arg Pro Tyr Lys Glu Lys Pro Val                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:25:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:25:                                - Thr Pro Leu Asn Pro Asp Asp Asp Phe Arg Pr - #o Gly                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:26:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:26:                                - Ser Pro Lys Ser Lys Pro Phe Ala Thr Asp Se - #r Gly Ala Met Pro His         #                15                                                           - (2) INFORMATION FOR SEQ ID NO:27:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:27:                                - Ala Pro Gln Phe Val Gln Asn Ile Pro Ala                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:28:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 6 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:28:                                - Lys Glu Leu Arg Pro Gln                                                     1               5                                                             - (2) INFORMATION FOR SEQ ID NO:29:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:29:                                - Ala Pro Glu Val Lys Phe Asn Lys Pro Phe Va - #l                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:30:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:30:                                - Ser Pro Leu Phe Ile Gly Lys Val Val Asn Pr - #o Thr                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:31:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:31:                                - Ser Lys Pro Ala Gly Lys Leu Thr Lys Ser Ly - #s Pro Gln Ala                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:32:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:32:                                - Ser Lys Pro Ala Gly Lys Leu Thr Lys Pro Ly - #s Pro Gln Ala                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:33:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:33:                                - Lys Ile Pro Ala Asn Trp Lys Lys Gln Phe Pr - #o Ala                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:34:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:34:                                - Val Pro Val Ala Ser Thr Asp Arg Trp Ser Gl - #u Leu Thr Glu Ala             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:35:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:35:                                - Ile Pro Arg Asn Glu Ala Asp Gly Met Pro Il - #e                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:36:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:36:                                - Ala Pro Ser Gln Ala Leu Gln Leu Ala Pro Al - #a                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:37:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:37:                                - Ala Pro Ala Leu Gln Pro Thr Gln Gly Ala Me - #t Pro Ala                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:38:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:38:                                - Ile Pro Trp Ala Pro Leu Ser Ser Ala Pro Se - #r                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:39:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:39:                                - Ser Pro Glu Leu Gly Pro Thr Leu                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:40:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:40:                                - Thr Pro Leu Gly Pro Ala Ser Ser Leu Pro Gl - #n Ser                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:41:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:41:                                - Leu Pro Leu Ala Thr Ala Ala Pro Thr Arg Hi - #s Pro Ile                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:42:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:42:                                - Asp Pro Val Val Ser Ser Thr Leu Ser Pro Gl - #u                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:43:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:43:                                - Val Pro Gly Met Asp Val Leu Pro Ser                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:44:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:44:                                - Ser Pro Glu Pro Arg Leu Phe Thr Pro Glu                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:45:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:45:                                - Tyr Pro Asp Glu Ile Glu Tyr Ile Phe Lys Pr - #o Ser                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:46:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:46:                                - Ser Pro Asp Lys Gln Ala Ala Ala Leu Pro Ar - #g Arg                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:47:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:47:                                - Asn Pro Glu Asn Ser Arg Pro Lys                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:48:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:48:                                - Thr Pro Ala Leu Phe Pro Lys                                                 1               5                                                             - (2) INFORMATION FOR SEQ ID NO:49:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:49:                                - Asn Pro Ala Gly Trp Thr Gly Asn Pro Asn                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:50:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:50:                                - Ala Pro Ile Tyr Asn Ala Asp Glu Leu Ile Pr - #o Arg                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:51:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:51:                                - Tyr Thr Pro Asn Trp Gly Arg Gly Asn Pro As - #n Asn                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:52:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:52:                                - Gly Asn Pro Asn Asn Phe Ile Asp Thr Val Th - #r Phe Pro Lys Val             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:53:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:53:                                - Leu Pro Val Thr Asp Ile Phe Ala Ala Pro Ly - #s                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:54:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:54:                                - Ala Pro Val Lys Glu Ala Asn Gln Pro Thr                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:55:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:55:                                - Thr Pro Ala Thr Glu Leu Thr Val Pro Asp                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:56:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:56:                                - Ser Pro His Glu Lys Asp Thr Arg Pro Leu                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:57:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:57:                                - Val Pro Gln Ala Glu Asn Gln Asp Pro Asp Il - #e                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:58:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:58:                                - Arg Pro His Arg Phe Leu Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:59:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:59:                                - His Phe Pro Gly Asn Leu Pro Asn Met Leu                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:60:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:60:                                - Thr Pro Ala Ile Asp Leu Leu Glu Thr Tyr Ly - #s Tyr Gly Asp Pro Ile         #                15                                                           - (2) INFORMATION FOR SEQ ID NO:61:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:61:                                - Asp Pro Ile Tyr Lys Glu Ala Lys Asp Arg Le - #u Met Thr Arg                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:62:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:62:                                - Asn Pro His Lys Ile Thr Asn Glu Arg Ile Ly - #s                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:63:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:63:                                - Glu Leu Arg Ala Lys Leu Asp Leu Ile Leu Pr - #o Asp                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:64:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:64:                                - Ser Pro Val Val Lys Glu Glu Asn Lys Val Gl - #u Glu Pro Gln Leu             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:65:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:65:                                - Lys Pro Thr Asn Asn Lys Trp Trp Ile Ile Pr - #o Ala                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:66:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:66:                                - Ala Pro Ser Gly Trp Ser Ser Tyr Glu Gly As - #n Pro Tyr                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:67:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:67:                                - Asn Pro Phe Val Ala Lys Ser Pro Ala                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:68:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:68:                                - Arg Pro Arg Gly Asn Thr Leu Ser Pro Ala                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:69:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:69:                                - Gly Pro Ser Val Arg Gly Asn Thr Leu Ser Pr - #o Ala                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:70:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:70:                                - Ala Pro Ala Lys Leu Lys Ala Pro Gly                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:71:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:71:                                - Ala Pro Gly Ser Ser Asn Tyr Arg Val Thr Ph - #e Ala Pro Thr Ala             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:72:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:72:                                - Gly Pro Thr Glu Tyr Ser Arg Phe Phe Lys Ar - #g Leu Ala Pro Asp             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:73:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:73:                                - Asp Lys Pro Thr Thr Val Thr Ala Pro Gly                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:74:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:74:                                - Asn Val Pro Met Asn Phe Ser Pro Thr Thr                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:75:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:75:                                - Ile Arg Pro Ala Met Lys Lys Thr Ile Tyr Gl - #u Asn Glu                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:76:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:76:                                - Arg Pro Arg Lys Leu Leu Arg Phe Asn Gly Pr - #o Val                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:77:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:77:                                - Gln Pro Arg Arg Pro Ala Leu Arg Gln Pro Al - #a                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:78:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:78:                                - Ala Pro Asn Gln Leu Arg Gln Val Asp Arg Pr - #o Ala                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:79:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:79:                                - Ile Pro Asn Ile Gly Ala Ala Pro Phe Arg Al - #a Trp                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:80:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:80:                                - Ile His Arg Arg Ala Gln Phe Gly Gly Gln Pr - #o Asp                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:81:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:81:                                - Leu Pro Asn Ile Ala Asn Ile Pro Asn                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:82:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:82:                                - Asp Arg Pro Leu Ala Phe Phe Pro Glu Asn Pr - #o Lys Glu                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:83:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:83:                                - Thr Thr Pro Asn Gly Thr Phe Val Ala Pro Ar - #g Val                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:84:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:84:                                - Tyr Gly Pro Val Leu Trp Ser Leu Gly Pro As - #n Gly                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:85:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:85:                                - Ser Pro Ala Ala Lys Thr Pro Lys Arg                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:86:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:86:                                - Leu Pro Gly Arg Glu Leu Val Arg Ala Gln Il - #e Ala Ile Pro Gly             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:87:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:87:                                - Leu Pro Gly Arg Glu Leu Val Arg Ala Val Il - #e Gln Ile Pro Gly             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:88:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:88:                                - Asp Pro Tyr Ile Arg Ile Gln Gly Leu Asp Va - #l Pro Lys Leu                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:89:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:89:                                - Glu Arg Pro Gly Ala Phe Pro Ser Glu                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:90:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:90:                                - Glu Pro Thr Lys Ala Gly Arg Gly Ala Ser Gl - #n Pro Ala                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:91:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:91:                                - Thr Pro Val Asn Ala Thr Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:92:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:92:                                - Thr Pro Ala Ile Arg His Pro Ala                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:93:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:93:                                - Phe Pro Asn Asn Leu Asp Lys Leu Pro Gly                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:94:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:94:                                - Gly Pro Asn Val Thr Asp Phe Pro Ser                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:95:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:95:                                - Lys Arg Pro Gly Trp Lys Leu Pro Asp Asn                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:96:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:96:                                - Met Pro Glu Glu Ser Ala Val Glu Pro Ser                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:97:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:97:                                - Asp Pro Gln Ala Arg Asp Pro Leu Lys Gly Th - #r Pro Asn                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:98:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:98:                                - Thr Pro Asn Gly Asn Arg Asp Gly Asn Thr Le - #u Pro Val                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:99:                                           -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:99:                                - His Pro Gly Ile Ala Glu Phe Pro Ser Arg Al - #a                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:100:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:100:                               - Ala Pro Ser Gly Gly Ser Pro Thr                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:101:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:101:                               - Ile Pro Leu Met Gln Gly Asn Leu Pro Thr                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:102:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:102:                               - Asp Pro Glu Met Leu Asn Arg Leu Ser Asp Pr - #o Val                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:103:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:103:                               - Leu Pro Thr Leu Thr Leu Ser Pro Lys                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:104:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:104:                               - Asp Pro Ile Lys Arg Ile Gln Asp Asp Ala Pr - #o Lys Ala                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:105:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:105:                               - Val Pro Ala Phe His Tyr Glu Ser Gln Asn Se - #r Thr Leu Pro Ile             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:106:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:106:                               - Trp Pro Phe Gly Asn Val Leu Pro Lys                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:107:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:107:                               - Leu Pro Pro Phe Leu Leu Asp Ala Ala Pro Al - #a                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:108:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:108:                               - Glu Pro Glu Ser Leu Glu Ile Asn Lys Pro Ty - #r                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:109:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:109:                               - Lys Pro Pro Gln Tyr Ile Ala Val His Val Va - #l Pro Asp Gln                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:110:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 14 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:110:                               - Asn Pro Trp Thr Val Phe Gln Lys Arg Leu As - #p Pro Ser Val                 #                10                                                           - (2) INFORMATION FOR SEQ ID NO:111:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 6 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:111:                               - Pro Ser Gly Ser Ala Pro                                                     1               5                                                             - (2) INFORMATION FOR SEQ ID NO:112:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 6 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:112:                               - Pro Arg Val Thr Asp Pro                                                     1               5                                                             - (2) INFORMATION FOR SEQ ID NO:113:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:113:                               - Pro Arg Gly Arg Gly Met Pro Gln Pro                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:114:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:114:                               - Glu Met Lys Ala Ser Lys Pro Gly Trp Trp Le - #u                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:115:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:115:                               - Leu Pro Gly Ser Phe Lys Thr Leu Glu Met Ly - #s Ala Ser Lys Pro Gly         #                15                                                           - (2) INFORMATION FOR SEQ ID NO:116:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:116:                               - Glu Met Leu Pro Ser Lys Ala Gly Ile Trp Ar - #g                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:117:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:117:                               - Tyr Pro Gly Val Phe Glu Thr Val Glu Met Le - #u Pro Ser                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:118:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:118:                               - Tyr Glu Lys Ala Gly Lys Met Gly Ala Trp Pr - #o Tyr                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:119:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 13 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:119:                               - Trp Pro Tyr Leu Thr Leu Tyr Lys Tyr Lys Al - #a Ser Ala                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:120:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 18 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:120:                               - Ser Pro Trp Gln Val Met Leu Phe Arg Lys Se - #r Pro Gln Glu Leu Leu         #                15                                                           - Pro Gly                                                                     - (2) INFORMATION FOR SEQ ID NO:121:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:121:                               - Leu Pro Arg Lys Ser Pro Gln Glu Leu Leu Pr - #o Gly                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:122:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:122:                               - Ile Pro Lys His Ser Arg Thr Arg Tyr Pro Ar - #g Asn Ile Glu Lys             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:123:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 17 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:123:                               - Ala Pro Trp Gln Ala Leu Leu Ile Asn Glu Gl - #u Asn Glu Gly Phe Pro         #                15                                                           - Gly                                                                         - (2) INFORMATION FOR SEQ ID NO:124:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:124:                               - Leu Pro Asn Glu Glu Asn Glu Gly Phe Pro Gl - #y                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:125:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:125:                               - Leu Pro Asn Glu Glu Asn Glu Pro Phe                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:126:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:126:                               - Val Pro Asp Arg Asn Thr Glu Gln Glu Glu Pr - #o Gly                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:127:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:127:                               - Phe Pro Trp Gln Val Val Leu Asn Gly Lys Va - #l Asp Ala Phe Pro Gly         #                15                                                           - (2) INFORMATION FOR SEQ ID NO:128:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:128:                               - Asn Pro Lys Val Asp Ala Phe Pro Gly                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:129:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 15 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:129:                               - Ala Pro Glu His Asn Ile Glu Glu Thr Glu Hi - #s Thr Glu Pro Lys             #                15                                                           - (2) INFORMATION FOR SEQ ID NO:130:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:130:                               - Ala Pro Trp Gln Val Leu Leu Leu Val Asn Gl - #y Ala Gln Leu Pro Gly         #                15                                                           - (2) INFORMATION FOR SEQ ID NO:131:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 16 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:131:                               - Ala Pro Trp Gln Val Leu Leu Leu Val Asn Pr - #o Ala Gln Leu Pro Gly         #                15                                                           - (2) INFORMATION FOR SEQ ID NO:132:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 12 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:132:                               - Leu Pro Glu His Asp Leu Ser Glu His Asp Pr - #o Asp                         #                10                                                           - (2) INFORMATION FOR SEQ ID NO:133:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:133:                               - Ala Pro Leu His Asp Phe Tyr Pro Ser                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:134:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:134:                               - Gln Pro Asn Asp Gly Gln Pro His                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:135:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:135:                               - Pro Tyr Gly Gly Phe Met Pro                                                 1               5                                                             - (2) INFORMATION FOR SEQ ID NO:136:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:136:                               - Pro Tyr Gly Gly Phe Leu Pro                                                 1               5                                                             - (2) INFORMATION FOR SEQ ID NO:137:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Phe at position 2ATION:                                              #Phe(4-tetrazole)"resents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:137:                               - Pro Phe Met Gly Trp Met Asp Phe Pro                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:138:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 5 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:138:                               - Pro Lys His Gly Pro                                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:139:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:139:                               - Pro Gln Thr Ala Ile Gly Val Gly Ala Pro                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:140:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:140:                               - Pro Glu Glu Ala Tyr Ile Pro Lys                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:141:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 5 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:141:                               - Pro Pro Phe Arg Pro                                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:142:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 6 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:142:                               - Arg Pro Asp Gly Trp Pro                                                     1               5                                                             - (2) INFORMATION FOR SEQ ID NO:143:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:143:                               - Pro Val Glu Glu Ala Glu Asn Pro                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:144:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 11 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:144:                               - Pro Lys Asn Phe Phe Trp Lys Thr Phe Thr Pr - #o                             #                10                                                           - (2) INFORMATION FOR SEQ ID NO:145:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:145:                               - Pro His Trp Ala Val Gly His Leu Pro                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:146:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 6 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4ATION:                                              #Ala or Gly"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5ATION:                                              #Glu or Asp"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:146:                               - Xaa Pro Xaa Xaa Xaa Xaa                                                     1               5                                                             - (2) INFORMATION FOR SEQ ID NO:147:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4ATION:                                              #Ala or Gly"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at positions 5TION:                                              #Glu or Asp"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6ATION:                                              #Tyr, Phe or Trp"presents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa at position 8ATION:                                              #Ala or Gly"   represents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:147:                               - Xaa Pro Xaa Xaa Xaa Xaa Pro Xaa                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:148:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Ser or Thr"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Xaa at position 2ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4ATION:                                              #Ala or Gly"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5ATION:                                              #Ala or Gly"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 7                                                     #/note= "Xaa at position 7ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa at position 8ATION:                                              #Ser or Thr"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa at position 9ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:148:                               - Xaa Xaa Pro Xaa Xaa Xaa Xaa Xaa Xaa                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:149:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 8 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Xaa at position 2ATION:                                              #Ala or Gly"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3ATION:                                              #Gln or Asn"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4ATION:                                              #Ser or Thr"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6ATION:                                              #Ser or Thr"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa at position 8ATION:                                              #Ala or Gly"   represents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:149:                               - Xaa Xaa Xaa Xaa Xaa Xaa Pro Xaa                                             1               5                                                             - (2) INFORMATION FOR SEQ ID NO:150:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 9 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3ATION:                                              #Ala or Gly"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4ATION:                                              #Lys, Arg, Homoarg, or Orn"                                                   -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5ATION:                                              #Glu or Asp"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 7                                                     #/note= "Xaa at position 7ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa at position 8ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 9                                                     #/note= "Xaa at position 9ATION:                                              #Ala or Gly"   represents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:150:                               - Xaa Pro Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                         1               5                                                             - (2) INFORMATION FOR SEQ ID NO:151:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 2                                                     #/note= "Xaa at position 2ATION:                                              #Lys, Arg, Homoarg or Orn"                                                    -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3ATION:                                              #Ser or Thr"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5ATION:                                              #Gln or Asn"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6ATION:                                              #Glu or Asp"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 7                                                     #/note= "Xaa at position 7ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 8                                                     #/note= "Xaa at position 8ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                    #/note= "Xaa at position 10TION:                                              #Ala or Gly"   represents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:151:                               - Xaa Xaa Xaa Pro Xaa Xaa Xaa Xaa Pro Xaa                                     #                10                                                           - (2) INFORMATION FOR SEQ ID NO:152:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 7 amino                                                           (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3ATION:                                              #Gln or Asn"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4ATION:                                              #Glu or Asp"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5                                                     #/note= "Xaa at position 5ATION:                                              #Glu or Asp"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 6                                                     #/note= "Xaa at position 6ATION:                                              #Gln or Asn"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 7                                                     #/note= "Xaa at position 7ATION:                                              #Glu or Asp"   represents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:152:                               - Xaa Pro Xaa Xaa Xaa Xaa Xaa                                                 1               5                                                             - (2) INFORMATION FOR SEQ ID NO:153:                                          -      (i) SEQUENCE CHARACTERISTICS:                                          #acids    (A) LENGTH: 10 amino                                                          (B) TYPE: amino acid                                                          (D) TOPOLOGY: linear                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 1                                                     #/note= "Xaa at position 1ATION:                                              #Ala or Gly"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 3                                                     #/note= "Xaa at position 3ATION:                                              #Tyr, Phe or Trp"presents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 4                                                     #/note= "Xaa at position 4ATION:                                              #Gln or Asn"   represents                                                     -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 5..9                                                  #/note= "Xaa at positions 5-9ON:                                              #Leu, Ile, Val, Met or Norleu"                                                -     (ix) FEATURE:                                                                     (A) NAME/KEY: Modified-sit - #e                                               (B) LOCATION: 10                                                    #/note= "Xaa at position 10TION:                                              #Gln or Asn"   represents                                                     -     (xi) SEQUENCE DESCRIPTION: SEQ ID NO:153:                               - Xaa Pro Xaa Xaa Xaa Xaa Xaa Xaa Xaa Xaa                                     #                10                                                           __________________________________________________________________________

What is claimed is:
 1. A method of producing aconformationally-constrained polypeptide that mimics the activity of astem cell factor, wherein the method comprises:producing theconformationally-constrained polypeptide, wherein theconformationally-constrained polypeptide contains a protein-proteininteraction site of said stem cell factor adjacently flanked on bothtermini by proline residues in a manner distinct from the manner foundin the stem cell factor.
 2. The method according to claim 1, wherein theproline residues are placed within 7 amino acid residues of the terminusof the protein-protein interaction site.
 3. The method according toclaim 2, wherein the proline residues are placed within 4 amino acidresidues of the terminus of the protein-protein interaction site.
 4. Themethod according to claim 3, wherein the proline residues are placedwithin 1 amino acid residue of the terminus of the protein-proteininteraction site.
 5. The method according to claim 1, wherein theconformationally-constrained polypeptide comprises no more than 30 aminoacid residues.
 6. The method according to claim 5, wherein theconformationally-constrained polypeptide comprises no more than 25 aminoacid residues.
 7. The method according to claim 6, wherein theconformationally-constrained polypeptide comprises no more than 15 aminoacid residues.
 8. The method according to claim 1, wherein the producingis performed with a peptide synthesizer.
 9. A method of producing aconformationally-constrained polypeptide that mimics the activity of astem cell factor, wherein the method comprises:synthesizing theconformationally-constrained polypeptide, wherein theconformationally-constrained polypeptide (i) has a different length thansaid stem cell factor and (ii) contains a protein-protein interactionsite of said stem cell factor, wherein the interaction site is flankedon both termini by proline residues.
 10. The method according to claim9, wherein the conformationally-constrained polypeptide comprises nomore than 30 amino acid residues.
 11. The method according to claim 10,wherein the conformationally-constrained polypeptide comprises no morethan 25 amino acid residues.
 12. The method according to claim 11,wherein the conformationally-constrained polypeptide comprises no morethan 15 amino acid residues.
 13. The method according to claim 9,wherein the synthesizing is performed with a peptide synthesizer.